Nicotinamide adenine dinucleotide (NAD+) biosynthetic and signaling system (NAD+ system)

The NAD+ biosynthetic enzymes and dehydrogenase/ADP-ribosyltransferase systems constitute a vital metabolic and signaling network centered on nicotinamide adenine dinucleotide (NAD+). This system includes biosynthetic enzymes like Nicotinamide phosphoribosyltransferase (NAMPT) and Nicotinamide mononucleotide adenylyltransferases (NMNATs), which maintain cellular NAD+ pools, and consuming enzymes such as Poly(ADP-ribose) polymerases (PARPs), Sirtuins (SIRTs), and CD38 (Canto et al., 2015, Cell Metabolism). NAD+ acts as a critical coenzyme for dehydrogenases in the TCA cycle and glycolysis, while also serving as a substrate for signaling enzymes that regulate DNA repair, gene expression, and calcium mobilization (Garten et al., 2015, Nature Reviews Cancer). Dysregulation of this system is linked to aging, metabolic disorders, and cancer, where NAD+ depletion or overconsumption can lead to mitochondrial dysfunction or genomic instability (Yoshino et al., 2018, Cell Metabolism). Therapeutic strategies include PARP inhibitors for oncology to induce synthetic lethality and NAD+ precursors like Nicotinamide Riboside (NR) to combat age-related physiological decline (Rajman et al., 2018, Cell). Because this 'target' encompasses multiple distinct enzyme families with opposing functions, therapeutic intervention requires high specificity to avoid disrupting essential homeostatic redox reactions.

Other names

NAD+ metabolomeNAD+ biosynthetic pathwayNAD+ consuming enzymesNicotinamide adenine dinucleotide metabolic network

Inhibition of NAD+ consuming enzymes (e.g., PARP inhibitors) to prevent DNA repair in BRCA-mutant cells; Inhibition of rate-limiting biosynthetic enzymes (e.g., NAMPT inhibitors) to deplete cellular ATP and NAD+ in cancer; Supplementation with NAD+ precursors to restore mitochondrial function and activate sirtuins.